International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

Effect of Mixed Solvent and Surfactants on the Dissociation Constant of Paracetamol

B. Acharya1 and P. K. Behera2
2

PKA College of Engg, Bargarh, India School of Chemistry, Sambalpur University, Burla, India

Abstract: Association and dissociation constants (pK) indicate the proportions of

different ionic species of a substance in a particular environment. Dissociation constants are very important both in the interpretation of the mechanisms of action of drugs and in their analysis. Dissociation constant helps to explain chemical phenomena such as absorption, distribution and elimination of substances. The prominent feature of organized assemblies such as micelles, reversed micelles, micro emulsions, vesicles etc, is the use of amphiphilic compounds which create a barrier between two immiscible phases, providing compartmentalization for the substrates of different affinity to various solvents. Shift in equilibrium is observed for the drug in aqueous as well as micellar media. At higher pH paracetamol deprotonates to form anionic specie. Polarity of the medium and surfactant behaviour affects the dissociation of the drug. Keywords: : pK, Absorption maxima, Organized assemblies, Surfactant, Paracetamol.

INTRODUCTION
Acid dissociation constants (i.e. pKa values) can be a key parameter for understanding and quantifying chemical phenomena such as reaction rates, biological activity, biological uptake, biological transport and environmental fate. Artificially organized assemblies such as micelles, reversed micelles, micro emulsions, vesicles etc, have been used extensively to mimic biological system [1-3]. Acid-Base equilibrium in micellar media differ significantly from that in the aqueous media [4-6]. Micellar media can dissolve substances with low solubility in water thus modify acid-base or redox properties of the solutes. These aspects can be of interest in connection with the increasing use of aqueous micellar systems as solvents in analytical chemistry [7] and as bio membrane models [8]. Micelles can affect the apparent pKa values of the reagents due to combination of electrostatic and micro environmental effects of the micelles [9-11]. Dissociation constants are very important both in the interpretation of the mechanisms of action of drugs and in their analysis. pK of a drug helps to explain chemical phenomena such as the site of absorption, distribution to various organs and excretion [12-14]. It also helps in screening salts, developing preclinical and clinical formulation [15-17], in developing analytical methods like HPLC [13]. In biochemistry the pKa values of proteins and amino acid side chains are of major importance for the activity of enzymes and the stability of proteins. In pharmacology, ionization of a compound alters its physical behaviour and macro properties such as solubility and lipophilicity. This is exploited in drug development to increase the concentration of a compound in the blood by adjusting the pKa of an ionizable group. pK indicates the proportions of different ionic species of a substance in a particular environment [18]. These parameters are being utilized 47
Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

as dependent variables in many quantitative structure-activity relationships (QSAR) in biological phenomenon. Different ionic species have different electronic spectra. Significant spectrophotometry can be done and the value of pK can be calculated at each pH using the Hendersons equation. In this work the pK of paracetamol, an analgesic drug & its absorption behaviour is investigated in aqueous, methanol-water, 1,4-dioxane-water systems & also in varying concentration of SDS, CTAB and TX-100 surfactants below and above critical micellar concentration at different pH in the range of 6.0-13.60 at (270.1oC).

MATERIALS AND METHODS

Paracetamol was used after crystallization from Methanol. Sodium Dodecyl sulphate (SDS; Sigma) was crystallized twice from alcohol before use. Cetyl Trimethyl Ammonium Bromide (CTAB; Sigma) was purified by dissolving it in 1:9 Methanols, Acetone mixture. Triton X-100 (TX-100: Merck) was used as such. 1,4-Dioxane was allowed to stand for one day over Sodium metal and distilled over Sodium, Methanol was distilled. Buffer solutions with varied pH (6-13.6) were used. Concentrated (1x10 -3M) stock solutions of paracetamol were prepared by dissolving weighed sample of the drug in Millipore water. Concentrated stock solutions of SDS, CTAB and TX-100 were prepared by dissolving known weight of the surfactant in triple distilled water. The concentration of the surfactants was maintained below & above CMC. Absorption spectra were recorded on Hitachi-2800 UV-visible spectrophotometer at 3000.1 K. The sensitivity of the equipment is in the range of 0.1 nm. The pH of the analytical solution was measured by using Elico model II-120 digital pH meter with glass-calomel combination electrodes. The pH meter was standardized by phthalate buffer (pH= 4.0), phosphate buffer (pH = 6.85) and borate buffer (pH = 9.18) with an error of 0.1.

RESULT AND DISCUSSION

The pK of paracetamol have been investigated in its solution with water and also in various mixtures of methanol + water (80%, 60%, 40%, 20% and 10%) and dioxane + water (80%, 40%, 20% and 10%) mediums with varying pH. It can be seen from the Fig. 1 & 2(a-b) that at neutral pH i.e. 7.0 the absorption maxima of paracetamol (max) in different medium is around 241 nm. As the pH increases from 7.0 to 13.60 i.e. (neutral to basic) the max shifts from 241 to 258 nm i.e. it shows a bathochromic shift. In neutral pH paracetamol show peak for the neutral species and as the pH increases, deprotonation of paracetamol starts and at higher pH it shows the peak due to anion. The dissociation of paracetamol is shown in Scheme-1.

Scheme-1: Deprotonation of paracetamol in alkaline medium. 48

Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

The dissociation constants of paracetamol are det ermined from the plot of max vs. pH and also using the Hendersons equation.

pK a pH log

Ab Ax Ax Ab

where, Ax = Absorbance of the compound at any pH, Aa = Absorbance of strongly acid solution of the compound and Ab = Absorbance of strongly alkaline solution of the compound. Representative absorption spectra of the drug in varied pH in aqueous, various mixtures MeOH and Dioxane in water respectively are shown in Fig.1 & 2(a,b).

Fig.1: Absorption spectra of paracetamol in water at various pH at 250C.

Fig. 2(a): Absorption spectra of paracetamol with varying pH

Fig. 2(b): Absorption spectra of paracetamol with varying pH

The plots of Absorbance maxima (max) vs. pH of the drug in aqueous as well as different medium with varied pH are given in Fig.3(a)-(i). The pK values of paracetamol calculated from the plot and also using Handersons equation in alkaline (pK) pH are reported in Table.1 49
Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

Fig.3(a): Aq. Medium

Fig.3(b): 80% MeOH

Fig.3(c): 40% MeOH

Fig.3 (d): 20% MeOH

Fig.3 (e): 10% MeOH

Fig.3 (f): 80% Dioxane

Fig.3 (g): 40% Dioxane

Fig.3 (h): 20% Dioxane

Fig.3 (i): 10% Dioxane

Table 1: pK values of paracetamol in different medium at 27 0C. Medium Water 10% MeOH 20% MeOH 40% MeOH 80% MeOH 10% Dioxane 20% Dioxane 40% Dioxane 80% Dioxane pK From the plot 9.86 10.06 10.27 10.55 10.75 10.56 10.68 10.98 11.53 50
Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

Water 10% MeOH 20% MeOH 40% MeOH 80% MeOH 10% Dioxane 20% Dioxane 40% Dioxane 80% Dioxane

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

It can be seen from the Table-1 that the pK values of paracetamol increases with decrease in water percentage. Due to decrease in solvent polarity, (Dielectric constant of H2O is 76, MeOH is 32 and that of 1,4-Dioxane is 2.3) dissociation of paracetamol (R-OH R-O) decreases as it is more stable in polar medium. The absorption spectra and plot of max vs. pH for paracetamol in SDS, CTAB & TX-100 surfactants above and below the CMC are given in Fig. 5 & Fig. 6(a)-(i) respectively. The dissociation constants of the drug for various surfactants are calculated from the plot and also using Hendersons equation in alkaline pH are reported in Table.2.

Fig.5: Uv-vis spectrum of the drug in different surfactant.

Fig.6(a): 4x10-3 M SDS.

Fig.6(b): 1x10-2 M SDS.

Fig.6(c): 3x10-2 M SDS.

51
Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

Fig.6(d): 4x10 M CTAB.

-4

Fig.6(e): 1x10 M CTAB.

-3

Fig.6(f): 3x10-3 M CTAB.

Fig.6(g): 1x10-4 M TX-100.

Fig.6(h): 1x10-3 M TX-100.

Fig.6(i): 3x10-3 M TX-100.

Table 2: pK values of paracetamol in surfactants below & above CMC. pK Surfactant [Surfactant] From the plot From Hendersons Equation 4x10-3M SDS [CMC=8x10-3] TX-100 [CMC=3x10-4] CTAB [CMC=8x10-4] 1x10-2M 3x10-2M 1x10-4M 1x10-3M 3x10-3M 4x10-4M 1x10-3M 3x10-3M 10.67 10.41 10.70 10.38 10.15 10.45 10.29 10.14 09.87 10.780.02 10.680.04 11.060.03 10.630.03 10.480.03 10.700.04 10.480.02 10.260.04 10.030.06

The pK values of the drug range from 10.05 to 10.70 in different environments. Below CMC the trend of pK values of paracetamol is pK(SDS) > pK(TX-100) > pK(CTAB). This may be due to stability of conjugate base (RO) in various surfactant solutions. In SDS the dissociation from R-OH R-O- decreases as R-O- is unstable due to electrostatic repulsion between anionic head group of SDS and R-O- whereas in case of cationic CTAB dissociation increases as R-O- is stable due to electrostatic attraction between cationic head group of CTAB and R-O-. In SDS, with increase in micellar concentration above CMC, the pK values increases because the electrostatic repulsion between the R-O- and anionic head group of the surfactant hinders the dissociation of R-OH R-O-. In CTAB, the pK value decreases as the micellar concentration increases above CMC because the electrostatic attraction between the R-O- and cationic head 52
Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India

International Journal of Creative Mathematical Sciences & Technology (IJCMST) 2(1): 47-53, 2012

ISSN (P): 2319 7811, ISSN (O): 2319 782X

group of the surfactant increases which facilitates the dissociation of R-OH R-O- hence pK value decreases. In case of TX-100 the pK value does not vary much due to absence of electrostatic force.

CONCLUSION
The polarity of the medium and nature of the surfactant (cationic, anionic & non ionic) plays an important role on the dissociation of paracetamol.

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Corresponding Author: B. Acharya, PKA College of Engg, Bargarh, Odisha, India